In Alzheimer's disease, somatostatin-like immunoreactivity is significantly diminished, concommitant with a decline in the amount of acetylcholine and the activity of choline acetyltransferase in the cortex and hippocampus. A functional association between somatostatin and acetylcholine is also suggested by a number of observations in normal rat brain. It is of interest therefore to determine the neurochemical action of somatostatin. Our previous work has shown that somatostatin and analogs inhibit the phosphorylation of specific synaptic plasma membrane (SPM) proteins in proportion to their degree of affinity for brain membrane binding sites. This inhibition of SPM protein phosphorylation differs from that seen in response to ACTH with regard to sensitivity of membrane extracts and correlation with behavioral effects (induction of grooming behavior). This research proposal will characterize the nature of the functional interaction which exists between somatostatin and acetylcholine. To achieve this goal and to develop a possible animal model of Alzheimer's disease, rats will be treated with cysteamine to lower levels of brain somatostatin. Cortex extracts will be analyzed for somatostatin content using a radioimmunoassay for the peptide. During the period of somatostatin depletion, cortex SPM fractions will be prepared and endogenous protein phosphorylation plus/minus added somatostatin will be examined and compared to the patterns obtained from normal rats. Choline acetyltransferase activity, an index of cholinergic function, will be measured in cortex homogenates from rats treated acutely and chronically with cysteamine to determine possible influences of somatostatin on acetylcholine function in this brain region. In converse experiments, hippocampal SPM protein phosphorylation plus/minus somatostatin will be examined in fornix-lesioned rats, in which the loss of cholinergic presynaptic terminals is indicated by the loss of choline acetyltransferase activity in hippocampal homogenates following the lesion. Results so obtained are important not only because they provide information regarding the functional interaction of a neurotransmitter and a peptide at the synaptic level, but also because the findings might be relevant to the basic neuronal alterations seen during Alzheimer's disease and senile dementia of the Alzheimer's type.